{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T10:40:00Z","timestamp":1773916800949,"version":"3.50.1"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","award":["PL2024H045"],"award-info":[{"award-number":["PL2024H045"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>\n                    For decades, the sarco\/endoplasmic reticulum Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ATPase 2 (SERCA2) in skeletal muscle was primarily recognized for its role in orchestrating slow-twitch muscle fiber relaxation\u2014an essential process dependent on its ability to actively sequester cytoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    into the sarcoplasmic reticulum (SR) lumen, thereby sustaining intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis critical for muscle contraction-relaxation cycles. However, recent genetic and molecular biology studies have expanded the function of SERCA2 to a core hub integrating Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling, metabolic homeostasis, and endoplasmic reticulum (ER) stress. This novel function is underpinned by a sophisticated multi-layered regulatory network spanning from transcription to post-translational, which ensures that SERCA2 expression and activity dynamically adapt to the dual demands of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis maintenance and metabolic signaling demands. Dysregulation of this network or mutations in the ATP2A2 gene have been linked to hereditary myopathies, while SERCA2 dysfunction is also a key driver of muscle atrophy and insulin resistance in pathological conditions such as chronic inflammation and obesity. As a metabolic hub, the core mechanism of SERCA2 lies in its role as a critical node connecting local Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling to systemic metabolism through regulating ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis and SERCA2-SLN uncoupling (mediating non-shivering thermogenesis). Therapeutic strategies targeting SERCA2, including small-molecule activators such as CDN1163, AAV9-SERCA2a gene therapy, mimetic peptides, and exercise interventions, have demonstrated potential in treating various systemic diseases by restoring the \u201ccalcium pump-metabolism\u201d dual functions of SERCA2. However, the hierarchical regulatory logic linking SERCA2\u2019s calcium-handling and metabolic functions remains fragmented, and subtype-specific therapeutic strategies are undefined. This review synthesizes recent breakthroughs to propose a unified \u201ccalcium-metabolism coupling\u201d framework and identifies translational gaps for precision targeting.\n                  <\/jats:p>","DOI":"10.3389\/fphys.2026.1775444","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T05:23:28Z","timestamp":1773897808000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From calcium pump to metabolic hub: emerging genetic phenotypes and metabolic networks of SERCA2 in skeletal muscle"],"prefix":"10.3389","volume":"17","author":[{"given":"Shunyi","family":"Lei","sequence":"first","affiliation":[{"name":"Third Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanlong","family":"Qu","sequence":"additional","affiliation":[{"name":"Third Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Trauma, Hand, Foot and Ankle Surgery, Baotou City Fourth Hospital","place":["Baotou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Nan","sequence":"additional","affiliation":[{"name":"Third Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyao","family":"Liu","sequence":"additional","affiliation":[{"name":"Third Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhao","family":"Pan","sequence":"additional","affiliation":[{"name":"Third Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaoyue","family":"Yu","sequence":"additional","affiliation":[{"name":"Third Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"111380","DOI":"10.1016\/j.cbi.2025.111380","article-title":"Modulatory roles of capsaicin on thermogenesis in C2C12 myoblasts and the skeletal muscle of mice","volume":"407","author":"Abdillah","year":"2025","journal-title":"Chem. 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